Interleukin (IL)-1, IL-6, and IL-8 Predict Mucosal Toxicity of Vaginal Microbicidal Contraceptives1

Abstract

Inflammation of the female reproductive tract increases susceptibility to HIV-1 and other viral infections and, thus, it becomes a serious liability for vaginal products. Excessive release of proinflammatory cytokines may alter the mucosal balance between tissue destruction and repair and be linked to enhanced penetration and replication of viral pathogens upon chemical insult. The present study evaluates four surface-active microbicide candidates, nonoxynol-9 (N-9), benzalkonium chloride (BZK), sodium dodecyl sulfate, and sodium monolaurate for their activity against human sperm and HIV, and their capacity to induce an inflammatory response on human vaginal epithelial cells and by the rabbit vaginal mucosa. Spermicidal and virucidal evaluations ranked N-9 as the most potent compound but were unable to predict the impact of the compounds on vaginal cell viability. Interleukin (IL)-1 release in vitro reflected their cytotoxicity profiles more accurately. Furthermore, IL-1 concentrations in vaginal washings correlated with cumulative mucosal irritation scores after single and multiple applications (P < 0.01), showing BZK as the most damaging agent for the vaginal mucosa. BZK induced rapid cell death, IL-1 release, and IL-6 secretion. The other compounds required either more prolonged or repeated contact with the vaginal epithelium to induce a significant inflammatory reaction. Increased IL-8 levels after multiple applications in vivo identified compounds with the highest cumulative mucosal toxicity (P < 0.01). In conclusion, IL-1, IL-6, and IL-8 in the vaginal secretions are sensitive indicators of compound-induced mucosal toxicity. The described evaluation system is a valuable tool in identifying novel vaginal contraceptive microbicides, selecting out candidates that may enhance, rather than decrease, HIV transmission.

Seminal Fluid Induces Leukocyte Recruitment and Cytokine and Chemokine mRNA Expression in the Human Cervix after Coitus

“…Similar patterns of cytokines have been detected in cervical fluid recovered in vivo, with variations in abundance attributed to resident microflora and infection, and incidence of cigarette smoking (36,37). In situ localization studies identify epithelial cells as the principal cellular source of GM-CSF (38,39), 40), and IL-8 (41,42) in the cervix.…”

Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study

“…N-9-induced vaginal inflammation has been linked to increased HIV activity via IL-1-mediated mechanisms [18]. A group of cytokines, some of which have been shown to be released from immortalized human vaginal epithelial cells in vitro and from rabbit vaginal mucosa after exposure to surfaceactive microbicide candidates [19], was evaluated to help determine their potential as an in vivo system for monitoring the undesirable proinflammatory effects of microbicides and other vaginal products. In this study, neither product appeared to have proinflammatory effects.…”

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

“…Culture medium collected every 24 h for 3 days was evaluated for the induction of inflammatory cytokines (interleukin-8 [IL-8], IL-1␣, IL-6, and tumor necrosis factor alpha [TNF-␣]) using enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN). These cytokines were chosen because they have been reported to be consistent indicators of cumulative mucosal toxicity and inflammatory responses (12). All samples were evaluated in triplicate except for the samples undergoing cytokine analysis, which were evaluated with six replicates (n ϭ 6).…”